Pyrroloquinazoline derivatives



United States Patent 3,271,400 PYRROLOQUINAZOLINE DERIVATIVES Jack Bernstein, New Brunswick, and Erviu R. Spitzmiller,

Highland Park, N.J., assignors, by mesne assignments, to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of Delaware N0 Drawing. Filed Aug. 17, 1964, Ser. No. 390,217 11 Claims. (Cl. 260256.4)

This invention relates to new chemical compounds and more particularly, to compounds of the formula (I):

CH -CH CI H N- (lower alklene)-B g! and pharmaceutically acceptable acid-addition and quaternary ammonium salts thereof, wherein R is hydrogen, lower alkyl (e.g., methyl, ethyl and isopropyl), halogen (e.g., chlorine and fluorine), halomethyl (e.g., trifluoromethyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy and amyloxy), aryloxy, (e.g., phenoxy), amino, or di- (lower alkyl)amino (e.g., dimethylamino and diethylamino); R is two hydrogens or a keto (0x0) group; and B is a basic nitrogen-containing radical such as amino, (lower alkyl) amino, di(lower alkyl)amino, (e.g., dimethylamino and diethylamino), hydroxy(lower alkyl)amino, di[hydroxy(lower alkyl) amino, halo(lower alkyl)amino, (lower alkyl aralkylamino, (e.g., methylphenethylamino) (e.g., benzylamino), piperidyl (e.g., piperidino), (lower alkyl)piperidyl (e.g., 2,3- and 4-methylpiperidino), dilower alkyl)piperidyl (e.g., 2,4-, 2,6- and 3,5-dimethylpiperi-dino); homopiperidyl; pyrrolidyl (e.g., pyrrolidino), (lower alkyl) pyrrolidyl, di(lower alkyl)pyrrolidyl, piperazinyl (e.g., piperazino), homopiperazinyl, (lower alkyl)- piperazinyl, (e.g., N -methylpiperazino), di(lower alkyl)- piperazinyl, (lower alkoxy)piperazinyl, arylpiperazinyl (e.g., R-substituted phenylpiperazino, such as 4-phenylpiperazino), aralkylpiperazinyl (e.g., R-substituted phenyL (lower alkyl)-piperazino, such as benzylpiperazino and p-chlorophenethylpiperazino, pyridylpiperazinyl [e.g., 4- 3-pyridyl)piperazino], pyridyl(lower alkyl)piperazinyl [e.g., 4-(3-pyridylrnethyl)piperazino], alkanoyloxy-lower alkyl)piperazinyl, [e.g., 4-(Z-acetoxyethyl)piperazino], (hydroxy-lower alkyl)piperazinyl, [e.g., 4-(2-hydroxyethyl)piperazino], homopiperazinyl, morpholinyl (e.g., morpholino), (lower alkyl)morpholinyl, di(lower alkyl) morpholinyl, thiamorpholinyl (e.g., thiamorpholino), (lower alkyl)thiamorpholinyl and di(lower alkyl)thiamorpholinyl. The terms lower alkyl, lower alkoxy, and lower alkylene as employed herein, included both straight and branched chain radicals of less than eight carbon atoms.

The preferred compounds of this invention are those of Formula I in which R is hydrogen, lower alkylene is ethylene, isopropylene or propylene, and B is di(lower alkyl) amine.

Examples of suitable acid-addition salts of the free bases of this invention include the mineral acid salts, such as the hydrohalides (e.g., hydrochloride, hydrobromide and hydroiodide), the sulfate and the phosphate; and organic acid salts, such as the citrate, tartrate, oxalate, ascorbate, acetate and succinate. Pharmacologically acceptable acids are of course employed where the salt form is prepared for therapeutic use.

Examples of suitable quaternary ammonium salts of the free bases of this invention include the lower alkyl halides ice (e.g., methyl chloride and methyl bromide), the lower alkyl sulfates (e.g., methosulfate), the aralkyl halides (e.g., benzyl chloride) and the aralkyl sulfates.

The compounds of this invention are physiologically active substances having hypotensive activity and central nervous system depressive activity. The compounds of this invention can be administered to reduce blood pressure perorally in the usual perorally acceptable forms, such as tablets and capsules, the dosage for such treatment being adjusted for the activity of the particular compound employed.

The compounds of this invention are prepared by the process of this invention which comprises reacting a compound of the Formula II:

wherein R is as hereinbefore defined, with a base such as an alkali metal hydride or amide (e.g., sodium hydride or sodamide or an alkali metal alkoxide such as sodium alkoxide or potassium t-butoxide to yield the alkali metal derivative; treating the alkali metal derivative with an amino(lower alkylene) halide (preferably chloride) of the formula: B-(lower alkylene) halide, wherein B is as hereinbefore defined, to yield the bases of this invention of the Formula I, wherein R is keto; and, if desired, reducing the keto group, as by treatment with lithium aluminum hydride, to yield those compounds of Formula I, wherein R is two hydrogen atoms. The bases of Formula I can then be converted to either their acid-addition salts or quaternary ammonium salts in the usual manner by treatment with the desired acid or quaternizing agent.

In those instances where the compounds of Formula II are new, they can be prepared by the method described by Bohme et al., Archiv. der Pharmazie, 294/66, 5 61 (1961), by reacting an anthranilamide of the formula wherein R is as hereinbefore defined, with 3-cl1lorobutyraldehyde-diethylacetal of the formula OCzH Cl(CH2)aCH in alcoholic hydrogen chloride medium to yield the corresponding 2(3-chloropropyl) 2,3-dihydro 4 (1-H)- quinazolinone hydrochloride of the formula and heating the hydrochloride with sodium hydroxide to form the 2,3,3a,4 te-trahydropyrrolo[i,2a]-quinazolin- 5(1H)-one of the formula The following examples illustrate the invention (all temperatures being in centigrade):

Example 1.4-(2-dimethylaminoethyl) -2,3,3a,4-tetrahydnopyrrl0[1,2-a] -quinaz0lin-5 (1H)-one A solution of 20.6 g. (0.11 mole) of 2,3,3a,4-tetrahydropyrroleELZ-a]quinazolin-(1H)-one in 300 ml. of dimethylformamide is added at 25 over a period of minutes to a stirred suspension of 5.7 g. (0.11 mole) of sodium hydride (in oil 50% dispersion) in 200 ml. of dimethylformamide. The addition is accompanied by elfervescence and a spontaneous rise in temperature to 35. After a clear, colorless reaction mixture is obtained (one hour), a solution of 23 g. (0.15 mole) of 2-dimethylaminoethyl bromide in 150 ml. of toluene is added all at once and stirring is continued for 18 hours. The solvents are then removed via a flash evaporator over a water bath at 70-80 at a pressure of 5 mm. The residue is cooled, layered over with 300 ml. of ether and 50 ml. of water is added. The etheral layer is removed and again washed with Water. The ether solution is extracted with cold 5% hydrochloric acid. The yellow acidic aqueous solution is cooled in an ice water bath and made strongly alkaline to pH indicator paper by the addition of solid potassium carbonate. The released free base is extracted into ether. After drying over magnesium sulfate and filtration, the ether is removed via a flash evaporator leaving a yellow solid residue weighing about 11 g. (44%) MP. about 94-98". 2.7 g. is recrystallized from '200 ml. of hexane with a recovery of about 1.8 g., M.P. about 9799.

Analysis.Calcd. for C H N O: C, 69.41; H, 8.16; N, 16.16. Found: C, 69.25; H, 8.34; N, 15.87.

Example 2.4-[3-(dimethylamin0)pr0pyl]-2,3,3a,4-tezrahydropyrrolo[1.2-0]-quinaz0lin-5(1H)-0ne, salt with one mole of oxalic acid, hemihydratc A solution of the sodium salt from 3.8 g. (0.02 mole) of 2,3,3a,4-tetrahydropyrro1o[1,2-a]quinazolin-5(1H)-one in 150 ml. of toluene containing 10 ml. of dimethylformamide is stirred with 3 g. (0.025 mole) of 3-dimethylaminopropyl chloride for 5 hours at 100-110. After cooling to room temperature, the reaction mixture is filtered and the solvents are removed by distillation. The oil residue weighing 5 g. is taken up in ether and 10 ml. of 3 N ethereal hydrogen chloride is added. The resulting hygroscopic orange colored hydrochloride salt is dissolved in water and the free base is released from the cooled aqueous solution with solid potassium carbonate and extracted into ether. After drying over magnesium sulfate and filtration, the solvent is removed via a flash evaporator leaving a yellow oil residue weighing about 3 g. The oil is taken up in 50 ml. of ethanol and a solution of 3 g. of oxalic acid (0.033 mole) in 50 ml. of ethanol is added. The oxalic acid salt which gradually crystallizes from solution is recrystallized from ethanol with a yield of about 2 g. (27%), MP. about 164-165" d.

Analysis.Calcd for C16H23N3O'C2H2O4'1/2H2OI N, 11.20; C, 58.11; H, 7.04; NE. 186. Found: N, 11.38; C, 58.05; H, 7.04; NE. 185.

Similarly, by substituting the following R-substituted- 2,3,3a,4-tetrahydropyrrolo[ 1,2-a] quinazolin-S 1H) ones for the 2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)- one in the procedure of Example 1, the indicated 4(2- dimethylaminoethyl)-R-substituted 2,3,3a,4 tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one is formed:

Rcactant (R is) Product Formed (R is) S-Trifiuoromethyl. 8-Trifiuor0methyl. 7-Meth0xy 7-Methoxy. 8-Phenoxy 8-Phenoxy G-Amino. 6 Amino 7-Diethylamino 7-Diethylamino.

Example 13,-4-(3-N-methylpiperazinopropyl) -2,3,3a,4- tetrahydropyrrolo- [1,2-a] -quinaz0lin-5(1H) -0ne Following the procedure of Example 1, but substituting 3-(N-methylpiperazino)propyl chloride for the Z-dimethylaminoethyl chloride, 4- (3 -N-methylpiperazinopropyl -2,3, 3a,4-tetrahydropyrrolo[1,2-a]-quinazolin 5(1H) one is formed.

Similarly, by substituting the following B-(lower alkylene) chlorides for the 2-dimethylaminoethyl chloride in the procedure of Example 1, the indicated 4-aminoalkyl- 2,3,3a,4-tetrahydropyrrolo-[1,2-a]-quinazolin-5(1H) one is obtained:

Example Reactant Product 3-Diethylaminopropyl.-.. 2 Methy1amin0ethyl 2-Diethylaminoethyl. 2-Bcnzylaminoethyl. Z-Piperidinoethyl 4-Pyrrolidinobutyl 3-Homopiperidonopropyl 2 (3-Piperidinyl)ethyl 3-(N-Pheuylpiperazino)- propyl. 3-[N-(2-HydroxyethyD- piperazino1propyl. 2-HomopiperazinoethyL.. G-Morpholinohexyl 3-Thiamorph0linopropyl.

Z-(Methylphenethylamino)-ethyl. 2-(Dimethy1amin0)propy1 3-Dicthylarninopropyl. 2-Methylaminoethyl. Q-Diethylaminocthyl. Z-Benzylaminoethyl. Z-Piperidinoethyl. 4-Pyrrolidinobutyl. 3-H0m0piperidinopropy1. 2-(3-Piperidinyl)ethyl. 3-(N-Phenylpiperazino)- piperazinolpropyl. 2-I'I0rnopiperazinoethyl. G-Morpholinohexyl. S-Thiamorpholinopropyl. 2-(Methylphenethylamino)-ethy1. 2-(Dimethylamino)propyl.

Example 29.4-(Z-a'imethylaminoethyl)-2,3,3a,4-te=trahydropyrrolo [1,2-a]-quinaz0lin-5(1H)-0ne methochloride A solution of 150.0 g. of material from Example 1 in ml. of acetonitrile is cooled and treated with 25 g. of methyl chloride. After standing for several days at room temperature, the solution is diluted to 300 ml. with ether to give the methoohloride.

Example 30.-4-(2 dimethylaminoethyl) 1,2,3,3a,4,5-

hexahydropyrrolo [1,2-a]quinaz0line, salt with two males of oxalic acid A solution of 8 g. (0.03 mole) of 4-(2-dimethy1aminoethyl) 2,3,3a,4 tetrahydropyrnolo[1,2 a]qui.nazolin 5 (1H)-one in 500 ml. of ether is added over a period of 15 minutes to a stirred suspension of 2.3 g. (0.06 mole) of lithium aluminum hydride in 200 ml. of ether. Stirring at room temperature in an atmosphere of nitrogen is continued for 18 hours. After the cautious addition of 4.5 ml. of water followed by a solution of 1.5 g. of sodium hydroxide in 10 ml. of water, the ethereal solution is decanted and the solid residue is washed several times with ether. The ethereal solutions are combined and dried over magnesium sulfate. After filtration the ether is removed via a flash evaporator leaving an oil residue weighing about 6 g. The oil is taken up in 100 m1. of ethanol and a solution of 9 g. (0.1 mole) of oxalic acid in 100 ml. of ethanol is added. A pink colored solid separates immediately from solution. The solid is collected by suction filtration (11.5 g.) and is recrystallized from ethanol with a recovery of 7.5 g. Solvent retained by the solid from the recrystallization is removed by trituration with hot acetonitrile followed by washing with anhydrous ether.

Analysis.-Calcd. for C H N -C H O N, 9.87; C, 53.64; H, 6.40. Found: N, 10.12; C, 53.66; H, 6.40.,

Example Reactant (R is) Product Formed (R is) Q-ethyl.

7-rnethyl. 8-isopropyl. G-chloro. B-trilluorornethyl. 7-methoxy.

S-phenoxy.

7-methoxy. 8-phenoxy.

fi-amino. r 8-dimethyl amino 7-diethylamino G-amino. S-dimcthylamino. 7-dicthylamino.

Similarly, by substituting the following 4-arninoalky1- 2,3,3 a,4 tetrahydropyrrolo[1,2 a] quinazolin (1H)- ones for the 4-(2-dimethylaminoethyl-2,3,3a,4-tetrahydr0- pyrrolo[1,2-a]-quinazolin-5(1H)-one in the procedure of Example 30, the indicated 4-aminoalkyl-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a1-quinazoline (in the form of its oxalic acid salt is formed:

Example Reactant Product 3-diethylaminopropyl. 2-methylaminoetl1yl. 2-diethylaminoethyl.

3-dlethylamln0propyl Zmethylaminoethyl- Z-diethylarninoethyl Q-benzylamlnoethyl. 2-benzy1aminoethyl. 2-piperidinocthyl. 2-p1peridinoethyl.

4-pyrrolidinobutyl 4-pyrrolidinobutyl.

3-homopiperidinopropyl. 2-(3-piperidinyl)cthyl. 3-(N-phenylpiperazlno)- propyl. propyl. 3-[N-(2hydroxyethyD- 3 lN-(2- ydroxyethyD- piperazino1propyl. piperazino1propyl. 2-homopiperazinoethyl Z-hcmopiperazmoethyl. fi-morpholinohexyl (lrnorpholinohexyl. Il-thiamorpholinopropyl- 3-thiarnorpholinopropyl.

2-(methylphcncthylaniino)- 2-(mcthylphencthylamino)- ethyl.

2- (dimethylamino) propyl.

ethyl. 2-(dirnethy1amino)propyl The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound selected from the group consisting of bases of the formula N- (lower alkylene)-B and the pharmaceutically acceptable acid-addition and quaternary ammonium salts thereof, wherein R is selected from the group consisting of hydrogen, lower alkyl, halogen, halomethyl, lower alkoxy, mononuclear aryloxy, amino and di(lower alkyl)amino; R is selected from the group consisting of two hydrogens and keto; and B is a basic nitrogen-containing radical selected from the group consisting of amino, (lower alkyl)amino, di(lower alkyl)amino, hydroxy(lower alkyl amino, halo (lower alkyl) amino, di [hydroxy( lower alkyl) amino, (lower alkyl)phenyl (lower alkyl) amino, piperidyl, (lower alkyl)piperidyl, di(lower alkyl)piperidyl, homopiperidyl, pyrrolidyl, (lower alkyl) pyrrolidyl, di(lower alkyl) pyrrolidyl, piperazinyl, homopiperazinyl, (lower alkyl)piper azinyl, di(lower alkyl) piperazinyl, (lower alkoxy) piperazinyl, R-phenylpiperazinyl, R-phenyl(lower alkyl)piperazinyl, pyridylpiperazinyl, pyridyl (lower alkyl) piperazinyl, (lower alkanoyloxy-lower alkyl)piperazinyl, (hydroxy-lower alky1)piperazinyl, morpholinyl, (lower alkyl) morpholinyl di(1ower a1l yl)morpholinyl, thia-morpholinyl, (lower alkyl)thiamorpholinyl and di (lower alkyl thiamorpholinyl.

2. 4-[di(lower alkyl)amino(lower alky1)]-2,3,3a,4- tetrahydropyrrolo 1,2-a] quinazolin-S 1H) -one.

3. A pharmaceutically acceptable salt of the compound of claim 2.

4. 4-(2 dimethylaminoethyl) 2,3,3a,4-tetrahydro pyrrolo[1,2-a]quinazolin-5(1H)-one.

5. A pharmaceutically acceptable salt of the compound of claim 4.

6. 4-[3-(dimethylamino)propyl] 2,3,3a,4-tetrahydropyrrolo-[1,2,a]quinazolin-5(1H)-one.

7. A pharmaceutically acceptable salt of the compound of claim 6.

8. 4-[di(lower alkyl)amino(lower alkyl)]-1,2,3,3a,4,5- hexahydropyrrolo[1,2-a1quinazoline.

9. A pharmaceutically acceptable salt of the compound of claim 8.

1t). 4-(2-dimethylaminoethyl)-1,2,3,3a,4,5 hexahydropyrrolo-[1,2-a]quinazoline.

11. A pharmaceutically acceptable salt of the compound of claim 10.

Reterences Cited by the Examiner UNITED STATES PATENTS 2,621,162 12/1952 Baker 260--256.4

2,651,632 9/1953 Baker 260-256.4

OTHER REFERENCES Gaylord: Reduction with Complex Metal Hydrides, In-

terscience Publishers, New York, 1956,. pages 601, and 610-611.

ALEX MAZEL, Primary Examiner.

HENRY R. TILES, Examiner.

M. OBRIEN, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES OF THE FORMULA 